Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. Improved results in clinical transplantation have been achieved primarily through the development of increasingly potent nonspecific immunosuppressive drugs to inhibit rejection responses. While short-term results have, improved long-term outcomes remain inadequate. The development of strategies to promote transplantation tolerance, or the acceptance of allogeneic tissues without the need for chronic immunosuppression could not only reduce the risk of these life-threatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies, genetic immunodeficiencies, and possibly autoimmune diseases. Strategies to induce stable hematopoietic chimerism confer robust donor-specific tolerance. However, there are many practical issues that must be addressed for tolerance induction to become a clinical reality. There is an increasing body of evidence to suggest that an individual's past history of immune responses to antigen may influence the subsequent immune response to an allograft (heterologous immunity). The influence of heterologous immunity on transplant outcomes with chronic immunosuppression has been underappreciated and may prove to be an even greater issue for tolerance induction. Thus, it is critical that experimental models be developed in which to study the impact of an existing immunological memory to pathogens on the alloimmune response. The specific aims of this study are to: (1) To study the effects of heterologous immunity and allospecific memory cells generated after acute viral infections on the induction transplantation tolerance; (2) To study the effects of persistent productive and latent viral infections on tolerance induction and the effects of tolerance induction on the control of persistent productive and latent viral infections; and (3) To determine whether high-level mixed or complete hematopoietic chimerism results in deficiencies in the control of viruses that establish non-persistent, persistent-productive, or latent infections in immunocompetent hosts. This study will allow us to better protect allografted tissues and organs and ultimately to induce transplantation tolerance in a wider segment of the clinical population in need.